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Obatoclax inhibits SARS-CoV-2 entry by altered endosomal acidification and impaired cathepsin and furin activity in vitro
Coronavirus disease 2019 (COVID-19) caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has set off a global pandemic. There is an urgent unmet need for safe, affordable, and effective therapeutics against COVID-19. In this regard, drug repurposing is considered as a...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8843317/ https://www.ncbi.nlm.nih.gov/pubmed/34989664 http://dx.doi.org/10.1080/22221751.2022.2026739 |
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author | Mao, Binli Le-Trilling, Vu Thuy Khanh Wang, Kai Mennerich, Denise Hu, Jie Zhao, Zhenyu Zheng, Jiaxin Deng, Yingying Katschinski, Benjamin Xu, Shilei Zhang, Guiji Cai, Xuefei Hu, Yuan Wang, Jianwei Lu, Mengji Huang, Ailong Tang, Ni Trilling, Mirko Lin, Yong |
author_facet | Mao, Binli Le-Trilling, Vu Thuy Khanh Wang, Kai Mennerich, Denise Hu, Jie Zhao, Zhenyu Zheng, Jiaxin Deng, Yingying Katschinski, Benjamin Xu, Shilei Zhang, Guiji Cai, Xuefei Hu, Yuan Wang, Jianwei Lu, Mengji Huang, Ailong Tang, Ni Trilling, Mirko Lin, Yong |
author_sort | Mao, Binli |
collection | PubMed |
description | Coronavirus disease 2019 (COVID-19) caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has set off a global pandemic. There is an urgent unmet need for safe, affordable, and effective therapeutics against COVID-19. In this regard, drug repurposing is considered as a promising approach. We assessed the compounds that affect the endosomal acidic environment by applying human angiotensin-converting enzyme 2 (hACE2)- expressing cells infected with a SARS-CoV-2 spike (S) protein-pseudotyped HIV reporter virus and identified that obatoclax resulted in the strongest inhibition of S protein-mediated virus entry. The potent antiviral activity of obatoclax at nanomolar concentrations was confirmed in different human lung and intestinal cells infected with the SARS-CoV-2 pseudotype system as well as clinical virus isolates. Furthermore, we uncovered that obatoclax executes a double-strike against SARS-CoV-2. It prevented SARS-CoV-2 entry by blocking endocytosis of virions through diminished endosomal acidification and the corresponding inhibition of the enzymatic activity of the endosomal cysteine protease cathepsin L. Additionally, obatoclax impaired the SARS-CoV-2 S-mediated membrane fusion by targeting the MCL-1 protein and reducing furin protease activity. In accordance with these overarching mechanisms, obatoclax blocked the virus entry mediated by different S proteins derived from several SARS-CoV-2 variants of concern such as, Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2). Taken together, our results identified obatoclax as a novel effective antiviral compound that keeps SARS-CoV-2 at bay by blocking both endocytosis and membrane fusion. Our data suggested that obatoclax should be further explored as a clinical drug for the treatment of COVID-19. |
format | Online Article Text |
id | pubmed-8843317 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-88433172022-02-15 Obatoclax inhibits SARS-CoV-2 entry by altered endosomal acidification and impaired cathepsin and furin activity in vitro Mao, Binli Le-Trilling, Vu Thuy Khanh Wang, Kai Mennerich, Denise Hu, Jie Zhao, Zhenyu Zheng, Jiaxin Deng, Yingying Katschinski, Benjamin Xu, Shilei Zhang, Guiji Cai, Xuefei Hu, Yuan Wang, Jianwei Lu, Mengji Huang, Ailong Tang, Ni Trilling, Mirko Lin, Yong Emerg Microbes Infect Coronaviruses Coronavirus disease 2019 (COVID-19) caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has set off a global pandemic. There is an urgent unmet need for safe, affordable, and effective therapeutics against COVID-19. In this regard, drug repurposing is considered as a promising approach. We assessed the compounds that affect the endosomal acidic environment by applying human angiotensin-converting enzyme 2 (hACE2)- expressing cells infected with a SARS-CoV-2 spike (S) protein-pseudotyped HIV reporter virus and identified that obatoclax resulted in the strongest inhibition of S protein-mediated virus entry. The potent antiviral activity of obatoclax at nanomolar concentrations was confirmed in different human lung and intestinal cells infected with the SARS-CoV-2 pseudotype system as well as clinical virus isolates. Furthermore, we uncovered that obatoclax executes a double-strike against SARS-CoV-2. It prevented SARS-CoV-2 entry by blocking endocytosis of virions through diminished endosomal acidification and the corresponding inhibition of the enzymatic activity of the endosomal cysteine protease cathepsin L. Additionally, obatoclax impaired the SARS-CoV-2 S-mediated membrane fusion by targeting the MCL-1 protein and reducing furin protease activity. In accordance with these overarching mechanisms, obatoclax blocked the virus entry mediated by different S proteins derived from several SARS-CoV-2 variants of concern such as, Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2). Taken together, our results identified obatoclax as a novel effective antiviral compound that keeps SARS-CoV-2 at bay by blocking both endocytosis and membrane fusion. Our data suggested that obatoclax should be further explored as a clinical drug for the treatment of COVID-19. Taylor & Francis 2022-02-10 /pmc/articles/PMC8843317/ /pubmed/34989664 http://dx.doi.org/10.1080/22221751.2022.2026739 Text en © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Coronaviruses Mao, Binli Le-Trilling, Vu Thuy Khanh Wang, Kai Mennerich, Denise Hu, Jie Zhao, Zhenyu Zheng, Jiaxin Deng, Yingying Katschinski, Benjamin Xu, Shilei Zhang, Guiji Cai, Xuefei Hu, Yuan Wang, Jianwei Lu, Mengji Huang, Ailong Tang, Ni Trilling, Mirko Lin, Yong Obatoclax inhibits SARS-CoV-2 entry by altered endosomal acidification and impaired cathepsin and furin activity in vitro |
title | Obatoclax inhibits SARS-CoV-2 entry by altered endosomal acidification and impaired cathepsin and furin activity in vitro |
title_full | Obatoclax inhibits SARS-CoV-2 entry by altered endosomal acidification and impaired cathepsin and furin activity in vitro |
title_fullStr | Obatoclax inhibits SARS-CoV-2 entry by altered endosomal acidification and impaired cathepsin and furin activity in vitro |
title_full_unstemmed | Obatoclax inhibits SARS-CoV-2 entry by altered endosomal acidification and impaired cathepsin and furin activity in vitro |
title_short | Obatoclax inhibits SARS-CoV-2 entry by altered endosomal acidification and impaired cathepsin and furin activity in vitro |
title_sort | obatoclax inhibits sars-cov-2 entry by altered endosomal acidification and impaired cathepsin and furin activity in vitro |
topic | Coronaviruses |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8843317/ https://www.ncbi.nlm.nih.gov/pubmed/34989664 http://dx.doi.org/10.1080/22221751.2022.2026739 |
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